NO145308B - PROCEDURE FOR THE PREPARATION OF AURANOFINE - Google Patents

Description

The present invention relates to a hitherto unknown chemical process for the production of auranofin and its related compounds, which uses as the main starting material a 2,3,-4,6-tetra-0-acetylglycopyranosylthioether or thioester,

whose aglycone moiety (R) is a readily available leaving group such as a stabilized carbon ion or a readily available displaceable group such as an acyl group. This ether-

or the ester starting material is made to react with a reactive tertiary phosphine gold ester or sulphide.

Auranofin is an orally active antiarthritic agent useful in humans [J. With. Chem. 15 1095 (1972), U.S. patent no. 3,635,945]. According to these literature sources, auranofin is produced by reaction of an alkali metal salt of a 1-thio-B-D-glycopyranose with a trialkylphosphine gold halide. The present invention is believed to be completely different from these previously known methods.

The method according to the invention is illustrated by the following:

where R is triphenylmethyl, lower alkanoyl or Ag where n is 1 or 2, X is chlorine, bromine or iodine or, only when R is lower alkanoyl a compound of formula I is reacted with (C2H5)3PAUS-.

In the method according to the invention, the thioether or thioester reacts very easily with the tertiary phosphine gold reagent (II). As a rule, the reaction proceeds at approx. room temperature,' but temperatures up to the boiling point of the reaction mixture can be used. A preferred temperature range is from 25 to 75°C. The reaction time is until the reaction is finished, but can be from 1/2 hour up to several days depending on the temperature of the reaction and the reaction ability of the reagents. The tertiary phosphine gold halides are also more reactive than the sulphides and are not as readily available as the bi-tertiary phosphine gold halides.

In general, any inert organic solvent in which the reactants are soluble can be used, such as a general halogenated hydrocarbon solvent such as chloroform, carbon tetrachloride, ethylene tetrachloride or methylene chloride, a benzenoid solvent such as benzene, toluene or xylene, dimethylformamide, dimethylacetamide, ethereal solvents such as diethyl ether or dioxane , ethyl acetate, ethyl carbonate, dimethyl sulphoxide, lower alkanols such as methanol, ethanol or isopropanol. The lower chlorohydrocarbons

especially methylene chloride is preferred.

The reaction product auranofin is isolated in standard ways, e.g. by evaporating the solvent in vacuo if necessary to form crude auranofin, which is then purified by chromatography or fractional crystallization. The starting materials are either known or produced by reactions described in the following examples. All temperatures are °C.

Example 1

2, 3, 4, 6- tetra- O- acetyl- l- S- trityl- l- thio- B- D- glycopyranose

A pyridine solution (100 ml) of 35 g (0.096 mol) of 2,3,4,6-tetra-O-acetyl-l-thio-B-D-glycopyranose [Methods in Carbohydrate Chemistry, vol. 2, page 436 (1967) ] and 28 g (0.10 mol) of triphenylmethyl chloride were stirred at room temperature for 12 hours. The solution was then filtered and the pyridine removed under reduced pressure. The residue was dissolved in chloroform (350 mL), washed with water (5 x 100 mL) and the chloroform solution dried (magnesium sulfate). The solvent was removed under reduced pressure,

and the remaining oil was dissolved in methanol and cooled to give 17 g (29%) of crystalline 2,3,4,6-tetra-O-acetyl-1-S-trityl-1-thio-3-D-glycopyranose, mp 177 - 179°C, [α]^<5> (in% methanol) = -37.8°.

A chloroform solution (50 mL) of 3.0 g (4.9 mmol) of 2,3,4,6-tetra-O-acetyl-l-S-trityl-l-thio-B-D-glycopyranose and 1.95 g (4, 9 mmol) bromo(triethylphosphine)gold (I) [Aust. J. Chem. 19,

539 (1966)] was stirred at room temperature for 48 hours and then cooled for 48 hours. The solvent was removed under reduced pressure and the residue subjected to column chromatography (silica gel/5% ether-chloroform). Crystallization of the resulting crude product from methanol-water gave auranofin as white crystals, melting point 109 - 113°C [a]^5(1% methanol) = -55.7°.

By using stoichiometric amounts of p-methoxybenzyl chloride, benzyl chloride, o,p-dimethoxybenzyl chloride or p-bromobenzhydryl bromide instead of triphenylmethyl (trityl) chloride in the above reactions, auranofin is obtained.

Example 2

2, 3, 4, 6- tetra- O- acetyl- l- S- trityl- l- thio- B- D- glycopyranose

A pyridine solution (100 ml) of 35 g (0.096 mole) of 2,3,4,6-tetra-O-acetyl-l-thio-B-D-glycopyranose [Methods in Carbohyd-rate Chemistry, Vol. 2, 436 (1963)] and 28 g (0.10 mol) of triphenylmethyl chloride was stirred at room temperature for 12 hours. The solution was filtered and the pyridine removed under reduced pressure. The residue was dissolved in chloroform (350 ml), washed with water (5 x 100 ml) and the chloroform solution dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue dissolved in methanol and cooled to give 17 g (29%) of crystalline 2,3,4,6-tetra-O-acetyl-D-S-trityl-1-thio-Ø-D-glycopyranose, melting point 177 - 179°C, [a]^<5> (1% methanol) = -37.8°.

A methanol solution (30 mL) of 0.84 g (4.9 mmol) silver nitrate and 3.0 g (4.9 mmol) 2,3,4,6-tetra-O-acetyl-1-S-trityl-1-thio -Ø-D-glycopyranose was stirred at 35°C for 30 minutes. The solution was then diluted to 100 ml with ether and cooled to -20°C overnight. The resulting precipitate was removed by filtration, washed with ether and dried to yield 1.94 g (83%) of 2,3,4,6-tetra-O-acetyl-l-S-silver-l-thio-B-D-glycopyranose, m.p. 123 - 128°C.

A methanol solution (35 mL) of 1.94 g (4.1 mmol) of 2,3,4,6-tetra-O-acetyl-l-S-silver-l-thio-B-D-glycopyranose and 1.44 (4.1 mmol) chloro(triethylphosphine)gold (I) was stirred at room temperature for 1 hour. The solution was filtered and the solvent removed under reduced pressure. Chromatography of the residue (silica gel/chloroform) followed by crystallization from methanol-water gave auranofin, mp 108 - 110°C, [α]^<5> (1% methanol) = -55.8°.

Example 3

A chloroform solution (25 ml) of 0.61 g (1.5 mmol) of 2,3,4,6-tetra-O-acetyl-l-S-acetyl-l-thio-B-D-glycopyranose oa l.o g (.1, 5 mmol) bis(triethylphosphine gold) sulfide was heated under reflux overnight and the solvent removed under reduced pressure. Chromatography of the residue (silica gel, benzene-chloroform 0 to 100%) gives a yellow oil with the chloroform eluate. Preparative thin layer chromatography (silica gel, ether-2% acetone) followed by crystallization from methanol-water gives auranofin, melting point 110 - 111°C.

Example 4

A chloroform solution (25 mL) of 1.0 g (2.5 mmol) pentaacetylthioglycose and 1.15 g (2.5 mmol) bis(triethylphosphine)gold chloride was stirred at room temperature for 72 h and the solvent removed under reduced pressure. Chromatography of the residue (silica gel, benzene-chloroform 0 to 100%) gives an oil, which was further purified by preparative thin layer chromatography (silica gel, ether-2% acetone). Crystallization of methanol-water gives auranofin, melting point 98-101°C.

Claims (2)

1. Process for the production of auranofin, characterized in that a compound with the formula where Ac is acetyl, and R is triphenylmethyl, lower alkanoyl, or Ag, is reacted with a compound of the formula where n is 1 or 2, and X is Cl, J, Br, or, only when R is lower alkanoyl, is reacted with a compound of formula I with (<C>2<H>5)3PAUS-, in an inert organic solvent, in which the reaction participants are soluble, at from room temperature up to the boiling point of the reaction mixture. 2. Method according to claim 1, characterized in that the solvent is methylene chloride.